HMGA1 sensitizes esophageal squamous cell carcinoma to mTOR inhibitors through the ETS1-FKBP12 axis.

Esophageal carcinoma is amongst the prevalent malignancies worldwide, characterized by unclear molecular classifications and varying clinical outcomes. The PI3K/AKT/mTOR signaling, one of the frequently perturbed dysregulated pathways in human malignancies, has instigated the development of various inhibitory agents targeting this pathway, but many ESCC patients exhibit intrinsic or adaptive resistance to these inhibitors. Here, we aim to explore the reasons for the insensitivity of ESCC patients to mTOR inhibitors. We assessed the sensitivity to rapamycin in various ESCC cell lines by determining their respective IC50 values and found that cells with a low level of HMGA1 were more tolerant to rapamycin. Subsequent experiments have supported this finding. Through a transcriptome sequencing, we identified a crucial downstream effector of HMGA1, FKBP12, and found that FKBP12 was necessary for HMGA1-induced cell sensitivity to rapamycin. HMGA1 interacted with ETS1, and facilitated the transcription of FKBP12. Finally, we validated this regulatory axis in in vivo experiments, where HMGA1 deficiency in transplanted tumors rendered them resistance to rapamycin. Therefore, we speculate that mTOR inhibitor therapy for individuals exhibiting a reduced level of HMGA1 or FKBP12 may not work. Conversely, individuals exhibiting an elevated level of HMGA1 or FKBP12 are more suitable candidates for mTOR inhibitor treatment.

KMT2A Mutations and High Prevalence of dMMR-associated Mutational Signatures as Prognostic Indicators in Metastatic Colorectal Cancer.

The conventional treatment strategies for patients with metastatic colorectal cancer (mCRC) are predominantly guided by the status of RAS and BRAF mutations. Although patients may exhibit analogous pathological characteristics and undergo similar treatment regimens, notable disparities in their prognostic outcomes can be observed. Therefore, tissue and plasma samples from 40 mCRC patients underwent next-generation sequencing targeting 425 cancer-relevant genes. Genomic variations and canonical oncogenic pathways were investigated for their prognostic effects in association with progression-free survival (PFS) of these patients. We found that patients with BRCA2 and KMT2A mutations exhibited worse prognostic outcomes after chemotherapy-based treatment (univariate, P < 0.01). Further pathway analysis indicated that alterations in the homologous recombination pathway and in the KMT2A signaling network were also significantly associated with shortened PFS (univariate, P < 0.01). Additionally, mutation signature analysis showed that patients with higher proportions of defective mismatch repair (dMMR)-related mutational signatures. Had a worse prognosis (univariate, P = 0.02). KMT2A mutations (hazard ratio [HR], 4.47; 95% confidence interval [CI], 1-19.93; P =0.050) and dMMR signature proportions (HR, 3.57; 95% CI, 1.42-8.96; P = 0.007) remained independently associated with PFS after multivariate analysis and the results were further externally validated. These findings may enhance our understanding of this disease and may potentially facilitate the optimization of its treatment approaches.

Diagnostic Performance of Angiography-Derived Quantitative Flow Ratio in Complex Coronary Lesions.

BACKGROUND: Quantitative flow ratio derived from computed tomography angiography (CT-QFR) and invasive coronary angiography (Murray law-based quantitative flow ratio [µQFR]) are novel approaches enabling rapid computation of fractional flow reserve without the use of pressure guidewires and vasodilators. However, the feasibility and diagnostic performance of both CT-QFR and µQFR in evaluating complex coronary lesions remain unclear. METHODS: Between September 2014 and September 2021, 240 patients with 30% to 90% coronary diameter stenosis who underwent both coronary computed tomography angiography and invasive coronary angiography with fractional flow reserve within 60 days were retrospectively enrolled. The diagnostic performance of CT-QFR and µQFR in detecting functional ischemia among all lesions, especially complex coronary lesions, was analyzed using fractional flow reserve as the reference standard. RESULTS: CT-QFR and µQFR analyses were performed on 309 and 289 vessels, respectively. The diagnostic sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for CT-QFR in all lesions at the per-vessel level were 91% (with a 95% CI of 84%-96%), 92% (95% CI, 88%-95%), 83% (95% CI, 75%-90%), 96% (95% CI, 93%-98%), and 92% (95% CI, 88%-95%), with values for µQFR of 90% (95% CI, 81%-95%), 97% (95% CI, 93%-99%), 92% (95% CI, 84%-97%), 96% (95% CI, 92%-98%), and 94% (95% CI, 91%-97%), respectively. Among bifurcation, tandem, and moderate-to-severe calcified lesions, the diagnostic values of CT-QFR and µQFR showed great correlation and agreement with those of invasive fractional flow reserve, achieving an area under the receiver operating characteristic curve exceeding 0.9 for each complex lesion at the vessel level. Furthermore, the accuracies of CT-QFR and µQFR in the gray zone were 85% and 84%, respectively. CONCLUSIONS: Angiography-derived quantitative flow ratio (CT-QFR and µQFR) demonstrated remarkable diagnostic performance in complex coronary lesions, indicating its pivotal role in the management of patients with coronary artery disease.

Efficacy, safety and genomic analysis of SCT200, an anti-EGFR monoclonal antibody, in patients with fluorouracil, irinotecan and oxaliplatin refractory RAS and BRAF wild-type metastatic colorectal cancer: a phase â ¡ study.

BACKGROUND: Limited therapeutic options are available for metastatic colorectal cancer (mCRC) patients after failure of first- and second-line therapies, representing an unmet medical need for novel therapies. METHODS: This is an open-label, single arm, multicenter, phase Ⅱ study aiming to perform the efficacy, safety and genomic analysis of SCT200, a noval fully humanized IgG1 anti-epidermal growth factor receptor (EGFR) monoclonal antibody, in patients with fluorouracil, irinotecan and oxaliplatin refractory RAS and BRAF wild-type mCRC. SCT200 (6 mg/kg) was given weekly for the first six weeks, followed by a higher dose of 8 mg/kg every two weeks until disease progression or unacceptable toxicity. Primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR) and secondary endpoints included ORR in patients with left-sided tumor, disease control rate (DCR), duration of response (DoR), time to response (TTR), progression-free survival (PFS), overall survival (OS) and safety. FINDINGS: From February 12, 2018 to December 1, 2019, a total of 110 patients aged between 26 and 77 years (median: 55; interquartile range [IQR]: 47-63) with fluorouracil, oxaliplatin, and irinotecan refractory RAS and BRAF wild-type mCRC were enrolled from 22 hospitals in China. As the data cut-off date on May 15, 2020, the IRC-assessed ORR and DCR was 31% (34/110, 95% confidence interval [CI] 22-40%) and 75% (82/110, 95% CI 65-82%), respectively. Thirty one percent (34/110) patients achieved confirmed partial response (PR). The median PFS and median OS were 5.1 months (95% CI 3.4-5.2) and 16.2 months (95% CI 11.1-not available [NA]), respectively. The most common ≥ grade 3 treatment-related adverse events (TRAEs) were hypomagnesemia (17%, 19/110) and acneiform dermatitis (11%, 12/110). No deaths occurred. Genomic analysis suggested positive association between MYC amplification and patients' response (P = 0.0058). RAS/RAF mutation and MET amplification were the most frequently detected resistance mechanisms. Patients with high circulating tumor DNA (ctDNA) at baseline or without ctDNA clearance at the 7th week after the first dose of SCT200 administration before receiving SCT200 had worse PFS and OS. INTERPRETATION: SCT200 exhibited promising clinical efficacy and manageable safety profiles in RAS and BRAF wild-type mCRC patients progressed on fluorouracil, irinotecan and oxaliplatin treatment. The baseline ctDNA and ctDNA clearance status at the 7th week after the first dose of SCT200 administration before receiving SCT200 could be a potential prognostic biomarker for RAS and BRAF wild-type mCRC patients with SCT200 therapy. FUNDING: This study was sponsored by Sinocelltech Ltd., Beijing, China and partly supported by the National Science and Technology Major Project for Key New Drug Development (2019ZX09732001-006, 2017ZX09304015).

Low-Temperature Upcycling of Polypropylene Waste into H2 Fuel via a Novel Tandem Hydrothermal Process.

Plastic waste is a promising and abundant resource for H2 production. However, upcycling plastic waste into H2 fuel via conventional thermochemical routes requires relatively considerable energy input and severe reaction conditions, particularly for polyolefin waste. Here, we report a tandem strategy for the selective upcycling of polypropylene (PP) waste into H2 fuel in a mild and clean manner. PP waste was first oxidized into small-molecule organic acids using pure O2 as oxidant at 190 °C, followed by the catalytic reforming of oxidation aqueous products over ZnO-modified Ru/NiAl2 O4 catalysts to produce H2 at 300 °C. A high H2 yield of 44.5 mol/kgPP and a H2 mole fraction of 60.5 % were obtained from this tandem process. The entire process operated with almost no solid residue remaining and equipment contamination, ensuring relative stability and cleanliness of the reaction system. This strategy provides a new route for low-temperature transforming PP and improving the sustainability of plastic waste disposal processes.

Akkermansia muciniphila protects the intestine from irradiation-induced injury by secretion of propionic acid.

Intestinal dysbiosis frequently occurs in abdominal radiotherapy and contributes to irradiation (IR)-induced intestinal damage and inflammation. Akkermansia muciniphila (A. muciniphila) is a recently characterized probiotic, which is critical for maintaining the dynamics of the intestinal mucus layer and preserving intestinal microbiota homeostasis. However, the role of A. muciniphila in the alleviation of radiation enteritis remains unknown. In this study, we reported that the abundance of A. muciniphila was markedly reduced in the intestines of mice exposed to abdominal IR and in the feces of patients who received abdominal radiotherapy. Abundance of A. muciniphila in feces of radiotherapy patients was negatively correlated with the duration of diarrhea in patients. Administration of A. muciniphila substantially mitigated IR-induced intestinal damage and prevented mouse death. Analyzing the metabolic products of A. muciniphila revealed that propionic acid, a short-chain fatty acid secreted by the microbe, mediated the radioprotective effect. We further demonstrated that propionic acid bound to G-protein coupled receptor 43 (GRP43) on the surface of intestinal epithelia and increased histone acetylation and hence enhanced the expression of tight junction proteins occludin and ZO-1 and elevated the level of mucins, leading to enhanced integrity of intestinal epithelial barrier and reduced radiation-induced intestinal damage. Metformin, a first-line agent for the treatment of type II diabetes, promoted intestinal epithelial barrier integrity and reduced radiation intestinal damage through increasing the abundance of A. muciniphila. Together, our results demonstrated that A. muciniphila plays a critical role in the reduction of abdominal IR-induced intestinal damage. Application of probiotics or their regulators, such as metformin, could be an effective treatment for the protection of radiation exposure-damaged intestine.

Development and validation of the chemotherapy-induced peripheral neuropathy integrated assessment - oxaliplatin subscale: a prospective cohort study.

BACKGROUND: Current chemotherapy-induced peripheral neuropathy (CIPN) assessment tools mostly have poor sensitivity and weak anti-interference, so that it is sometimes difficult to provide substantive guidance for clinical intervention. This study aimed to develop an assessment tool dedicated for oxaliplatin to address these limitations. METHODS: This study screened 445 OIPN-related literatures for producing a symptom list, and developed the questionnaire module through expert supplement, item generation, content correlation analysis, pre-testing, and item improvement. The validation phase used a Chinese population-based prospective cohort study from June 2021 to July 2022. Patients were requested to complete the tested questionnaire, QLQ-CIPN20 and the CTCAE grading one day before cycles 2-6 of chemotherapy. Cronbach's α coefficient and intraclass correlation coefficient (ICC) were calculated for the internal consistency and stability analysis, respectively. Exploratory factor analysis was conducted to investigate the construct validity. The correlations among the tested questionnaire, QLQ-CIPN20 and CTCAE were compared for the criterion validity analysis. Wilcoxon signed-rank sum test was utilized to compare the sensitivity between the tested questionnaire and QLQ-CIPN20. RESULT: A 20-item CIPN assessment tool named chemotherapy-induced peripheral neuropathy integrated assessment - oxaliplatin subscale (CIPNIA-OS) was developed. The validation phase included 186 patients. Cronbach's α coefficient of CIPNIA-OS was 0.764 (> 0.7), and ICC was 0.997 (between 0.9 and 1). The structure of CIPNIA-OS containing seven factors was examined. The correlation coefficient between CIPNIA-OS and CTCAE was 0.661 (95%CI 0.623 to 0.695), which was significantly higher than that between QLQ-CIPN20 and CTCAE (0.417, 95%CI 0.363 to 0.469, p < 0.01). Besides, the total score of CIPNIA-OS was mostly higher than QLQ-CIPN20, with an average difference of 2.189 (CI 95% 2.056 to 2.322), and the difference gradually expanded with the progress of chemotherapy (p < 0.05). CONCLUSION: This study developed an original CIPN questionnaire which was dedicated for OIPN assessment. It was a comprehensive tool that covered acute OIPN symptoms and integrated features from several proven CIPN assessment tools. The validation results supported that CIPNIA-OS had satisfactory reliability, stability, construct, criterion validity, and was more accuracy and sensitive than QLQ-CIPN20 in the evaluation of OIPN.

H2SO4 assisted hydrothermal conversion of biomass with solid acid catalysis to produce aviation fuel precursors.

With hydrothermal reaction, lignocellulosic biomass can be efficiently converted into furfural (FF) and levulinic acid (LA), both of which are key platform compounds that can be used for the subsequent preparation of aviation fuels. In order to reduce the acid concentration in traditional hydrolysis and provide a reaction system with good catalytic activity, we propose a biomass conversion route as dilute acid hydrolysis coupled with solid acid catalysis. Firstly, at different temperatures, the hemicellulose and cellulose in corn stover were step-hydrolyzed by sulfuric acid solution with a concentration of 0.9 wt. % to produce xylose and glucose, with conversion reaching 100% and 97.3%, respectively. Subsequently, a new resin-derived carbon-based solid acid catalyst was used to catalyze the aforementioned saccharide solutions to obtain FF with yield of 68.7 mol % and LA of 70.3 mol %, respectively. This work provides a promising approach for the efficient production of bio-aviation fuel precursors.

Sex Differences in Fractional Flow Reserve- or Intravascular Ultrasound-Guided Percutaneous Coronary Intervention.

BACKGROUND: A recent randomized trial reported fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) strategy was noninferior to the intracoronary ultrasound (IVUS)-guided PCI strategy with respect to clinical outcomes with fewer revascularizations. OBJECTIVES: This study sought to investigate the sex differences in treatment and clinical outcomes according to physiology- or imaging-guided PCI strategies. METHODS: In this secondary analysis of the FLAVOUR (Fractional Flow Reserve or Intravascular Ultrasonography to Guide PCI) trial, the impact of sex on procedural characteristics, PCI rate, and outcomes according to different strategies and treatment types (PCI vs deferral of PCI) was analyzed. The primary outcome was target vessel failure (TVF) at 24 months, defined as a composite of cardiac death, target vessel myocardial infarction, and target vessel revascularization. RESULTS: Of 1,619 patients, 30% were women. Compared with men, women had a smaller minimal lumen area, smaller plaque burden, and higher FFR. They had a lower PCI rate (40.8% vs 47.9%; P = 0.008), which was mainly contributed by FFR guidance. Overall, women showed a lower TVF rate (2.4% vs 4.5%). According to the treatment type, the cumulative incidence of TVF was lower in women than in men among those with the deferral of PCI (1.7% vs 5.2%). However, this trend was not observed in patients who underwent PCI. In both women and men, there were no differences in clinical outcomes between the FFR- and IVUS-guided strategies. CONCLUSIONS: In cases of intermediate stenosis, despite receiving fewer interventions, women had more favorable outcomes than men. The use of FFR led to a lower PCI rate but had a similar prognostic value compared with IVUS in both women and men.

Insight into pyrolysis mechanism of plastic waste with C-O/C-N bonds in the backbone.

Pyrolysis is an important method for efficiently recovering plastic monomers, fuels and chemicals from plastic waste. The depolymerization of the backbone structure of plastic waste is a key step of the pyrolysis process. Currently, researches on the pyrolysis mechanism of plastics with C-O/C-N bonds in the backbone are still not sufficiently in-depth and also lack systematic and comprehensive investigation. Therefore, this study for the first time comprehensively investigated both macroscopic and microscopic pyrolysis processes of plastics with C-O/C-N bonds in the backbone, and evaluated the difficulty of breaking different backbone linkages via bond dissociation energy (BDE) obtained by density functional theory (DFT) calculations to deeply reveal the pyrolysis mechanism. The results indicated that polyethylene terephthalate (PET) had a higher initial pyrolysis temperature and its thermal stability was slightly stronger than nylon 6. The backbone of PET was mainly decomposed via the cleavage of Cα-O on the alkyl side, while the degradation of nylon 6 backbone began with NH2 groups at the end of the backbone. The pyrolysis products of PET were mainly derived from the small molecular fragments, which were generated by the degradation of the backbone through the cleavage of CO bonds or CC bonds, while the pyrolysis products of nylon 6 were always dominated by caprolactam. In addition, based on the results of DFT calculations, it could be inferred that the cleavage of CC bond in PET backbone and the cleavage of its adjacent Cα-O were most likely to occur, which followed a competitive reaction mechanism. However, in pyrolysis of nylon 6, the conversion to caprolactam was mainly via the concerted reaction of amide CN bonds. Compared with the concerted cleavage of amide CN bond, the cleavage of CC bond in the backbone of nylon 6 was not predominant.

Comprehensive characterization of FBXW7 mutational and clinicopathological profiles in human colorectal cancers.

Background: FBXW7 is recognized as a critical tumor suppressor gene and a component of the ubiquitin-proteasome system, mediating the degradation of multiple oncogenic proteins, including c-MYC, Cyclin E, c-Jun, Notch, p53. Around 16% of colorectal cancer (CRC) patients carried FBXW7 somatic mutations, while a comprehensive characterization of FBXW7 somatic mutations in CRC is still lacking. Methods: Colorectal cancer patients with tumor samples and matching white blood cell samples in the past five years were screened and DNA sequenced. DNA sequencing data of MSK MetTropism cohort and RNA sequencing data of TCGA COAD cohort were analyzed. Results: We discovered that the FBXW7 mutations were associated with higher tumor mutation burden (TMB), higher microsatellite instability (MSI) score, and lower chromosomal instability (CIN) score. Patients with FBXW7 mutations showed better overall survival (HR: 0.67; 95%CI: 0.55-0.80, P < 0.001). However, patients with FBXW7 R465C mutation displayed worse overall survival in multi-variate cox analysis when compared with patients carrying other FBXW7 mutations (HR: 1.6; 95%CI: 1.13-3.1, P = 0.015), and with all other patients (HR: 1.87; 95%CI: 0.99-2.5, P = 0.053). Moreover, in MSI patients, the FBXW7 mutated group showed higher M1 macrophage, CD8+ T cell, and regulatory T cell (Tregs) infiltration rates, and significant enrichment of multiple immune-related gene sets, including interferon-gamma response, interferon-alpha response, IL6 JAK STAT3 signaling, p53 pathway. Conclusion: This analysis comprehensively identified FBXW7 alterations in colorectal cancer patients and uncovered the molecular, clinicopathological, and immune-related patterns of FBXW7-altered CRC patients.

Genetic Modulation of BET1L Confers Colorectal Cancer Susceptibility by Reducing miRNA Binding and m6A Modification.

Genetic variants in regions encoding 3' untranslated regions (UTR) of mRNA potentially alter miRNA binding affinity and N6-methyladenosine (m6A) levels to affect gene expression. A better understanding of the association of these variants with colorectal cancer susceptibility could facilitate development of cancer prevention and treatment approaches. Here, we analyzed miRNA expression profiles and integrated genetic analyses from 8,533 individuals to evaluate the effects of altered miRNA-binding sites on colorectal cancer risk. The single-nucleotide polymorphism rs11245997 in the BET1L 3'UTR was significantly associated with colorectal cancer risk. The rs11245997 A allele facilitated BET1L expression by disrupting miR-140-3p binding. It also reduced BET1L m6A modification, which upregulated BET1L expression levels through a mechanism mediated by the m6A methyltransferases (METTL14 and WTAP) and the m6A demethylase ALKBH5. Moreover, higher expression of BET1L was associated with advanced tumor stages and poor patient prognosis. Increased BET1L expression promoted growth of colorectal cancer cells in vitro and in vivo, which could be partially rescued with miR-140-3p overexpression. RNA sequencing and pathway analyses indicated that BET1L is associated with the steroid biosynthesis pathway through regulation of HSD17B7, CYP27B1, and COMT. These findings provide insights into the involvement of genetic variants of BET1L in the development and progression of colorectal cancer. SIGNIFICANCE: The integration of miRNA expression profiles and genetic variants identified rs11245997 as a colorectal cancer risk-related variant that reduces miR-140-3p binding and m6A modification, leading to BET1L upregulation to promote colorectal tumorigenesis.

Integrated multi-omics approach to distinct molecular characterization and classification of early-onset colorectal cancer.

Incidence of early-onset colorectal cancer (EOCRC), defined by a diagnosed age under 50 years, is increasing, but its heterogeneous etiologies that differ from general CRC remain undetermined. We initially characterize the genome, epigenome, transcriptome, and proteome of tumors from 79 patients in a Chinese CRC cohort. Data for an additional 126 EOCRC subjects are obtained from the International Cancer Genome Consortium Chinese cohort and The Cancer Genome Atlas European cohort. We observe that early-onset tumors have a high tumor mutation burden; increased DNA repair features by mutational signature 3 and multi-layer pathway enrichments; strong perturbations at effects of DNA methylation and somatic copy-number alteration on gene expression; and upregulated immune infiltration as hot tumors underlying immunophenotypes. Notably, LMTK3 exhibits ancestral mutation disparity, potentially being a functional modulator and biomarker that drives molecular alterations in EOCRC development and immunotherapies. This integrative omics study provides valuable knowledge for precision oncology of CRC.

Investigating the Eley-Rideal recombination of hydrogen atoms on Cu (111) via a high-dimensional neural network potential energy surface.

As a prototypical system for studying the Eley-Rideal (ER) mechanism at the gas-surface interface, the reaction between incident H/D atoms and pre-covered D/H atoms on Cu (111) has attracted much experimental and theoretical interest. Detailed final state-resolved experimental data have been available for about thirty-years, leading to the discovery of many interesting dynamical features. However, previous theoretical models have suffered from reduced-dimensional approximations and/or omitting energy transfer to surface phonons and electrons, or the high cost of on-the-fly ab initio molecular dynamics, preventing quantitative comparisons with experimental data. Herein, we report the first high-dimensional neural network potential (NNP) for this ER reaction based on first-principles calculations including all molecular and surface degrees of freedom. Thanks to the high efficiency of this NNP, we are able to perform extensive quasi-classical molecular dynamics simulations with the inclusion of the excitation of low-lying electron-hole pairs (EHPs), which generally yield good agreement with various experimental results. More importantly, the isotopic and/or EHP effects in total reaction cross-sections and distributions of the product energy, scattering angle, and individual ro-vibrational states have been more clearly shown and discussed. This study sheds valuable light on this important ER prototype and opens a new avenue for further investigations of ER reactions using various initial conditions, surface temperatures, and coverages in the future.

Cleanup of oils and organic solvents from contaminated water by biomass-based aerogel with adjustable compression elasticity.

Leakage of oils and organic solvents poses a significant threat to aquatic environments. Here, low-temperature carbonized aerogels with highly porous and anisotropic structures obtained only from biomass-derived materials were proposed to absorb polymorphic oils from contaminated water. Specifically, carbonized aerogels prepared at temperatures of 300 °C and 350 °C exhibited ultra-high absorption capacities (40‒125 g g-1) and oil-water separation efficiencies (> 99%) even in harsh environments, which were attributed to their exceptional properties, including high porosity, abundant macropores, excellent thermal stability, and hydrophobicity. Through citric acid crosslinking and low-temperature carbonization, the aerogels exhibited superior compression elasticity and could be cyclically utilized through simple extrusion while realizing the recovery of oils. Moreover, the outstanding photothermal conversion properties obtained through carbonization contributed to the high temperature and fluidity of the oils surrounding the aerogels, which is crucial for improving the absorption performance of high-viscosity oils. Such absorbent materials are used to separate crude oil from oil-water mixtures, which can achieve maximum absorption of 56 g g-1 and increase the absorption rate (from several days to 10 min) in a low-temperature (4 °C) seawater environment.

A Novel Glycolysis-Related Gene Signature Predicts Prognosis For Cutaneous Melanoma.

BACKGROUND: There exists a lack of effective tools predicting prognosis for cutaneous melanoma patients. Glycolysis plays an essential role in the carcinogenesis process. OBJECTIVE: We intended to construct a new prognosis model for cutaneous melanoma. METHODS: Based on the data from the TCGA database, we conducted a univariate Cox regression analysis and identified prognostic glycolysis-related genes (GRGs). Meanwhile, the GSE15605 dataset was used to identify differentially expressed genes (DEGs). The intersection of prognostic GRGs and DEGs was extracted for the subsequent multivariate Cox regression analysis. RESULTS: A prognostic signature containing ten GRGs was built, and the TCGA cohort was classified into high and low risk subgroups based on the risk score of each patient. K-M analysis manifested that the overall survival of the high-risk group was statistically worse than that of the lowrisk group. Further study indicated that the risk-score could be used as an independent prognostic factor that effectively predicted the clinical prognosis in patients of different ages, genders, and stages. GO and KEGG enrichment analysis showed DEGs between high and low risk groups were enriched in immune-related functions and pathways. In addition, a significant difference existed between high and low risk groups in infiltration pattern of immune cells and expression levels of inhibitory immune checkpoint genes. CONCLUSION: A new glycolysis-related gene signature was established for identifying cutaneous melanoma patients with poor prognoses and formulating individualized treatment.

Genetic variants in RNA m5 C modification genes associated with survival and chemotherapy efficacy of colorectal cancer.

BACKGROUND: Colorectal cancer is one of the most common malignant digestive tract tumors with a poor prognosis. RNA 5-methylcytosine (m5 C) is an important posttranscriptional widespread modification involved in many biological processes. However, the association between genetic variations of m5 C modification genes and the prognostic value of colorectal cancer remains unclear. METHODS: We investigated the association between candidate single nucleotide polymorphisms (SNPs) in 13 m5 C modification genes and colorectal cancer overall survival (OS) after chemotherapy by the Cox regression model. The combined effect of selected SNPs on OS, progression-free survival (PFS), and disease control rate (DCR) was assessed by the number of risk alleles (NRA). The GTEx and TCGA database were used to perform expression qualitative trait locus (eQTL) analysis. RESULTS: We identified that two SNPs in YBX1 were associated with OS after chemotherapy (HR = 1.43, p = 0.001 for rs10890208; HR = 1.36, p = 0.025 for rs3862218). A striking dose-response effect between NRA and OS after chemotherapy was found (ptrend  = 0.002). The DCR of patients receiving oxaliplatin chemotherapy in the 3-4 NRA group was markedly reduced in comparison to that in the 0-2 NRA group (OR = 1.49, p = 0.036). Moreover, YBX1 mRNA expression was significantly overexpressed in tumor tissues (p < 0.05) in the TCGA database, and eQTL analysis demonstrated that the two SNPs were associated with YBX1 (p = 0.003 for rs10890208 and p = 0.024 for rs3862218). CONCLUSION: Our study indicates that genetic variants in m5 C modification genes may mediate changes in YBX1 mRNA levels and affect the chemotherapeutic efficacy of colorectal cancer patients.

Low-temperature upcycling of PET waste into high-purity H2 fuel in a one-pot hydrothermal system with in situ CO2 capture.

The accumulation and improper disposal of a large amount of plastic waste have exacerbated the deterioration of the global ecosystem and environment. To simplify the complex management system and alleviate the environmental impact of plastic wastes, this study reports a novel one-pot hydrothermal conversion strategy for polyethylene terephthalate (PET), integrating three steps, namely depolymerization, subsequent in-situ aqueous phase reforming, and in-situ CO2 capture. Here, the PET waste was converted directly into the clean high-purity H2 fuel and the disodium terephthalate (Na2-TPA). A high yield of H2 at 23.7 mol/kgPET with ca. 99 % of H2 concentration was obtained at a temperature as low as 240 °C. The feasibility of this strategy in handling real-world PET plastic wastes was demonstrated through a series of tests on beverage bottles, food packaging, and polyester fabric waste. The Na2-TPA crystals produced from the proposed PET conversion system exhibited purity close to that of the standard sample, and thus had the potential to be directly used as an electrode material. Overall, this strategy provides an efficient way to transform PET waste into high-value products and improves the sustainability of the PET waste disposal process.

Pembrolizumab in Chinese patients with advanced melanoma: 3-year follow-up of the KEYNOTE-151 study.

Survival is generally poor for Chinese patients with advanced melanoma because of high rates of acral and mucosal melanoma and limited therapeutic options. The first analysis of the phase 1b KEYNOTE-151 study showed second-line pembrolizumab was well tolerated and had clinically meaningful antitumor activity in Chinese patients with advanced melanoma. Three-year follow-up is presented. Eligible patients were of Chinese descent and had unresectable stage III/IV melanoma that progressed after first-line therapy. Patients received pembrolizumab 2 mg/kg every 3 weeks for ≤35 cycles. Primary end points were safety and objective response rate (ORR). Secondary end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Response was assessed per RECIST v1.1 by blinded independent central review. Subgroup analyses were conducted by melanoma subtype and BRAF and PD-L1 status (acral melanoma only). 103 patients were enrolled; median follow-up duration (time from first dose to data cutoff [July 13, 2020]) was 44.6 months (IQR, 39.1-46.2). Any-grade treatment-related adverse events (TRAEs) occurred in 85.4% of patients, and grade 3/4 TRAEs in 12.6%. No grade 5 TRAEs occurred. Three patients discontinued pembrolizumab because of TRAEs (immune-mediated hepatitis, pneumonia, and arthritis). Immune-mediated AEs and infusion reactions occurred in 34.0% (grade 3/4, 2.9%). ORR was 17.6% (95% CI, 10.8-26.4; 1 complete response/17 partial responses), and median DOR was 13.8 months (range, 2.7-37.4+). Median PFS was 2.8 months (95% CI, 2.7-3.5) and 36-month PFS rate was 5.0%. Median OS was 13.2 months (95% CI, 10.4-16.5) and 36-month OS rate was 22.3%. Median OS for patients with known melanoma subtype was 14.8 months for acral, 13.5 months for nonacral cutaneous, and 7.4 months for mucosal melanoma. Among the acral subgroup, median OS was 22.8 months for PD-L1-positive disease, 8.4 months for PD-L1-negative disease, 18.5 months for BRAF wild-type disease, and 5.8 months for BRAF-mutant disease. Over 3 years' follow-up, second-line pembrolizumab continued to show manageable safety, clinically meaningful antitumor activity, and durable responses in Chinese patients with advanced melanoma. Subgroup analysis suggested particular benefit in PD-L1-positive and BRAF wild-type acral melanoma, although small subgroup sizes preclude definitive conclusions. Clinical trial registration: https://clinicaltrials.gov, identifier NCT02821000.

A first-in-human, phase 1a dose-escalation study of the selective MEK1/2 inhibitor FCN-159 in patients with advanced NRAS-mutant melanoma.

BACKGROUND: A phase 1a first-in-human study evaluated the safety/tolerability, preliminary antitumour activity and pharmacokinetics of the oral MEK1/2 inhibitor FCN-159 in Chinese patients with advanced, NRAS-mutant melanoma. PATIENTS AND METHODS: Patients received a single FCN-159 dose at assigned levels, proceeding to continuous dosing (once daily [QD] for 28-day cycles) if no dose-limiting toxicities (DLTs) occurred within the next 3 days. Dose escalation was initiated after review of data for the previous dose level. The primary end-point was incidence of DLTs after the first dose. RESULTS: Thirty-three patients were enrolled across nine FCN-159 dose groups (0.2-15 mg QD). One DLT occurred: grade 3 folliculitis in the 15-mg group. There was one grade >3 treatment-emergent adverse event (TEAE), death of unknown aetiology (not FCN-159 related). The most common FCN-159-related TEAE was rash (36.4%), and the incidence of grade ≥3 FCN-159-related TEAEs was 15.2%. Antitumour activity at QD doses <6 mg was limited; therefore, efficacy data are presented only for doses ≥6 mg (n = 21). The objective response and clinical benefit rates were 19.0% (four partial responses) and 52.4%, respectively. Median (95% confidence interval) duration of response and progression-free survival were 4.8 months (2.8-not reached) and 3.8 months (1.8-5.6), respectively. FCN-159 exposure increased dose-proportionately; geometric mean terminal half-life was 29.9-56.9 h. CONCLUSIONS: FCN-159 was well tolerated and demonstrated promising antitumour activity at doses ≥6 mg QD in patients with advanced, NRAS-mutant melanoma. The recommended phase 2 dose was 12 mg QD. GOV IDENTIFIER: NCT03932253. https://clinicaltrials.gov/ct2/show/NCT03932253.